The discovery of novel therapeutic agents has traditionally relied on the identification of biologically active secondary metabolites of microorganisms. These compounds have provided a rich source of natural products that have either been utilized directly as effective therapeutic agents, or have provided leads for novel therapeutic agents to be developed through synthetic techniques.
One disease for which the development of novel therapeutics is particularly important is cancer, which not only has eluded a “cure”, but is also one of the leading disease-related causes of death of the human population. Examples of anticancer agents that have been identified from or developed from natural sources include paclitaxel, mitomycin C, and adriamycin to name a few. One drawback to the use of secondary metabolites from natural resources, however, has been that these agents are generally only present in minute quantities. Fortunately, in an effort to make these agents more available for use, and to enable further pharmaceutical research, synthetic chemists have developed elegant and efficient synthetic strategies to enable the production of either the natural products themselves, or useful derivatives thereof.
Although these therapeutic agents, and others developed from natural sources, through the efforts of synthetic chemistry, are currently in use for the treatment of individuals having cancer, many of these agents, as well as other common treatments such as surgery and radiation, are often unselective for tumor cells and/or are so toxic as to render the individual significantly immunocompromised. Thus, although many strides have been made in the development of novel treatments, there remains a need for the identification of additional therapeutics, preferably those that are more selective and less toxic.
One particular family of natural products that has generated significant interest is the saframycins. The saframycins are a class of antibiotics with activity against gram-positive bacteria and also against several kinds of tumor. Specifically, several saframycin analogues have been isolated and characterized in recent years (see, DE 2839668; U.S. Pat. Nos. 4,248,863; 4,372,947; 5,023,184; 4,837,149; and EP 329606). For example saframycins A–H, R and S have been isolated from the culture broths of Streptomyces lavendulae, and saframycins Mx1 and Mx2, have been isolated from the culture broths of the myxobacterium, Myxococcus xanthus, each of the saframycins varying in the oxidation state of the ring system and in substitution of the core structure (see, for example, Saito et al. Chem. Pharm. Bull. 1995, 43, 777). It has been suggested that certain saframycins, namely A and C exhibit extreme cytotoxicity toward culture cells and toward several experimental tumors including leukemias L1210 and P388 and Ehrlich carcinoma. Specifically, saframycin A has been shown to block RNA synthesis in cultured cells, and it has been suggested that saframycins A and C exhibit this potency because of their ability to bind and cleave DNA (for a discussion of the biological activity of saframycins see, for example, Lown et al. Biochemistry 1982, 21, 419; Ishiguro et al. Biochemistry 1978, 17, 2545; Rao et al. Chem Res. Toxicol 1990, 3, 262; Ishiguro et al. J Biol. Chem. 1981, 256, 2162). Although this class of natural products has shown promising biological activity, there have been few investigations into the synthesis and development of novel analogues of this family of natural products (see, EP 233841; EP 173649; Fukuyama et al. J. Am. Chem. Soc. 1982, 104, 4957–4958; Kubo et al. J. Org. Chem. 1988, 53, 4295–4310; Fukuyama et al. J. Am. Chem. Soc. 1990, 112, 3712–3713).
Clearly, there remains a need to further investigate the potential of this class of natural products, and analogues thereof, to develop novel, more potent and more selective therapeutics. Additionally, because of the complexity of the structure of this class of natural products, there also remains a need to develop additional synthetic techniques to rapidly access novel compounds based upon the general core structure of the saframycins, and other related compounds.